According to the American Cancer Society an estimated 21,810 cases of primary malignant brain tumor will be reported in the US in 2008. The ACS also estimates that 13,070 deaths will occur due to these diseases in this year. This Phase II STTR program advocates the development of drugs for primary CNS cancers from the schweinfurthin family of natural products. The schweinfurthins are a family of natural products isolated by the National Cancer Institute and have a unique pattern of activity against cancer cell lines indicating a potentially untapped and novel mechanism of action. This project will undertake the further development of these agents by carrying out three specific aims: 1) we will synthesize 288 new bis-stilbene analogs of the schweinfurthins aimed at providing more structure function data, improving activity and physical properties for this class of compounds;2) we will test these compounds as they become available following an assay scheme developed in our Phase I feasibility studies, this will lead to testing of compounds in animal models of glioblastoma;and 3) we will undertake further hypothesis driven explorations of the mechanism of action of the schweinfurthins. The current clinical outcome of patients with glioblastoma and other aggressive CNS cancers makes development of new agents for these indications highly desirable. The three specific aims proposed here are designed to allow us to choose a candidate for IND enabling studies and to further our understanding of the mechanism of action of this novel family of compounds. PUBLIC HEALTH RELEVANCE: Primary glioma represents a significant challenge to the oncology community. While the incidence of glioma is relatively low at 5-10 per 100,000 individuals, therapeutic interventions for these diseases are of only marginal benefit. According to the American Cancer Society an estimated 21,810 cases of primary malignant brain tumor will be reported in the US in 2008. The ACS also estimates that 13,070 deaths will occur due to these diseases in this year. Research aimed at improving outcomes for this disease is clearly needed to address shortcomings in current therapies.